6-substituted-1, 2,4-pyrimido{8 4,5-e{9 thiadiazine-1,1-dioxides

ABSTRACT

Substituted 8-amino 1,2,4-pyrimido(4,5-e)-thiadiazines-1,1dioxides, e.g., 8-amino-3-ethyl-6-methylthio-1,2,4-pyrimido(4,5e)thiadiazine-1,1-dioxide, are prepared from substituted 4,6diamino-5-pyrimidine-sulfonamides and are useful as antihypertensives.

United States Patent [1 1 Anderson et al.

[ Aug 28, 1973 6-SUBSTITUTED- l 2,4-PYRIMIDO[4,5-E1THIADIAZINE-1,l-DIOXIDES inventors: Paul L. Anderson, Dover; Robert E.

Manning, Mountain Lakes, both of Assignee: Sandoz-Wander, lnc., Hanover,NJ.

Filed: Dec. 6, 1971 Appl. No.: 205,349

Related US. Application Data Continuation-impart of Ser. No. [93,555,Oct. 28, 1971, abandoned, which is a continuation-in-part of Ser. No.108,221, Jan. 20, 1971, abandoned.

US. Cl. 260/243 R, 424/246, 260/256.5 Int. Cl C07d 99/10 [58] Field ofSearch 260/243 R References Cited UNITED STATES PATENTS 9/1963 Bersteinet al 260/243 Primary Examiner-John M. Ford Attorney-Gerald D. Sharkin,Robert S. Honor et al.

12 Claims, No Drawings where where Z represents 0 or NH; and A and Beach represent hydrogen or A and B together represent a carbon tonitrogen bond, provided that when R is R S and A and B togetherrepresent a carbon to nitrogen double bond, R is other than hydrogen ormethyl; and that when R is RS and A and B are both hydrogen or when R ishydrogen and A and 8 together represent a carbon to nitrogen doublebond, R is other than hydrogen; and pharmaceutically acceptable acidaddition or alkali metla salts thereof. Compounds of formula (1) inwhich A and B represent hydrogen and R is other than R 80 may beprepared according to the following flow diagram:

R represents hydrogen or lower alkyl, i.e., alkyl havwhere where R islower alkyl as defined above and R" and R each independently representhydrogen or lower alkyl as defined above and; R represents hydrogen, RS,RSO or R represents hydrogen, lower alkyl as defined above, phenyl,cycloalkyl having three to six carbon atoms represents hydrogen, R 8- R,R, R R, R and R are as defined above provided R is other than hydrogen,when R" is R 8- where R is as defined above.

The compounds of formula (lb') are reduced to the correspondingcompounds of formula (la) with a metallic hydride reducing agent in asuitable inert solvent. The metallic hydride reducing agents which canbe used include sodium borohydride, butyl aluminum hydride, tertiarybutyl aluminum hydride and the like, preferably sodium borohydride.Although the reaction temperature is not critical, the reduction isconveniently carried out at temperatures between about 50 to 150C,preferably between C. and the reflux temperature of the system. Suitableinert solvents are preferably metallic hydride solublizing solvents suchas water, lower alkanols, such as methanol or ethanol, or mixtures ofwater and lower alcohols, although the particular solvent used is notcritical. For optimum results, the reaction should be run for about 2 to50 hours depending upon the steric hindrance of the R group. Theresulting product (la) is recovered by conventional techniques, e.g.,filtration.

Compounds of formula (I) in which A and B represent a carbon to nitrogenbond and R is other than are prepared according to the followingprocess:

where R is straight chain lower alkyl having one to three carbon atoms;

R" represents hydrogen, lower alkyl as defined above, phenyl, cycloalkylhaving three to six carbon atoms or R-" R and R are as defined above,provided R" is other than hydrogen or methyl when R is RS where R is asdefined above.

The compounds of formula (lb) are prepared by treating a compound offormula (II) with a trialkyl orthoalkanoate of formula (Ill). Although asolvent is not necessary, the reaction can be carried out using thelower alkanols indicated above or ethers, such as tetrahydrofuran,diethyl ether and the like, as solvents or preferably an excess of thecompound of formula (Ill). The temperature at which the reaction is runis not critical, but it is preferred that the process be carried out attemperatures between about 30 to 150C, preferably at the refluxtemperature of the system. The time of the reaction is not critical,although for optimum results, it is preferred that it be run for onehour or more. The final product (Ib) is recovered by conventionaltechniques, e.g. filtration and recrystallization.

The compounds of formula (lb) in which R is R 80 can and the compound ofla in which R is RfSO are prepared according to the following process:

where R, R, A and B are as defined above.

The compounds of formula (ld) are prepared by treating a compound offormula (lc) with an oxidizing agent in an organic acid solvent. Theparticular oxidizing agent used is not critical but chlorine or theperoxides, especially hydrogen peroxide are preferred. The organic acidsolvent in which the reaction is carried out can be an organic acid suchas acetic acid or propionic acid and the like, or mixtures of organicacid and water and/or organic acid anhydrides. The composition of thesolvent is not critical. The temperature at which the reaction is runalso is not critical, but it is preferred that the process be carriedout at temperatures between about 50 to 100C, preferably between 60 andC. The time of the reaction is not critical, although for optimumresults, it is preferred that it be run for one hour or more. The finalproduct (id) is recovered by conventional techniques, e.g., filtrationand recrystallization.

The compounds of formula (I) in which R is can also be preparedaccording to the following process:

it N l N R SO -kN and A, B, R, R, R, R, R and R are as defined above.

The compounds of formula (le) are prepared by treating a compound offormula (ld') with an amine of formula (IV). Although a solvent is notnecessary, the reaction can be carried out using the lower alkanols orthe ethers indicated above as solvents or an excess of the compound offormula (IV) when it is a liquid. The preferred solvents are the loweralcohols. The temperature at which the reaction is run is not criticalbut it is preferred that the process be carried out at temperaturesbetween about 20 to 100C., preferably between The compounds of formula(V) are prepared by acyl- 20 to 30 C. The time of the reaction is notcritical. ating a compound of formula (lla) with a compound of The finalproduct (le) is recovered by conventional formula VI in an inertsolvent. The acylation can be techniques, e.g., filtration andrecrystallization. carried out using the acid chloride or acid bromideCertain of the compounds of formula (I) may be pre- 5 form of compound(Vl) or by using the acid form of pared by the following reactionscheme: compound VI in conjunction with oxalyl chloride or bromide. Theinert solvent is preferably aromatic hydrocarbon, ethers such astetrahydrofuran, or excess compound (Vl), when liquid. Although thetempera- NH "N l0 ture is not critical, the reaction is normally carriedout 1 SOZNH2 I $02 at a temperature of 20 to 50C; preferably 20 to 30C.\I A The time is not critical, but the reaction should be run (I) L forabout 1 to 6 days for optimum results. The product N is recovered byconventional techniques, e.g., evaporation and recrystallization. (InThe compounds of formula (I) in which R and A and B are hydrogen mayalso be prepared by the following procedure:

where R represents hydrogen, lower alkyl as defined above, cycloalkylhaving three to six carbon atoms N111 .fill; or -RCl and o I 0: R ishydrogen, RS-, RSO or N NH Itcductirm x i .N'll

7 :I R4 l l \N (Id) (lg) R5 where where R, R and R and the proviso areas defined above R and R are as defined previously.

and with the further proviso that at least one of R The compounds offormula (lg) are prepared by reor R is other than hydrogen. ducing thecompounds of formula (ld) in a protolytic The compound of formula (lf)are prepared by cysolvent with a metallic hydride reducing agent. Theclizing a compound of formula (V) by heating. The cypreferred solvent iswater, but lower alcohols such as clizing may be carried out by heatingthe compound of methanol or ethanol or mixtures of water and loweralformula (V) to its melting point or by heating it when 4 cohols mayalso be used. The metallic hydride reducing R is other than R SO in thepresence of a strong agents which can be used include those set outabove base in water. The strong base can be ammonium hyfor thepreparation of compound (la) from compound droxide, sodium hydroxide orpotassium hydroxide. (lb'), especially sodium borohydride. Thetemperature The reaction with the base is generally carried out at atwhich the reaction is carried out is not critical, but between 75 to 110C for about 1 to 24 hours, although the reaction is generally run atbetween about 20C to the particular temperature and time are notcritical. C preferably 20 to 30C. Although the time is not The productis recovered by conventional techniques, critical, it is preferred thatthe reaction be run for at e.g., concentration and filtration. least 1hour. The product is recovered by conventional The compounds of formulaV are prepared in accor- 5o techniques, e.g., filtration. dance with thefollowing reaction scheme: The compounds of formula (I) in which R isNH: NH: RTN I I somu Ru N s :Nu: RWLLY N 0 I l l R:II \N/ Nu: R: areprepared in accordance with the following reac- (Im v (V) non Scheme:

SO; 1 so! N NE .\H h R l H l l w ere R7 .CI Iv R- n I :T R x Y ishydroxy or halo having an atomic weight of B B about 35 to and; A A

R and R"" are as defined previously (Ii) where R is lower alkyl asdefined above and,

R and R each independently represents hydrogen or lower alkyl and R A,and B are as defined above The compounds of formula (1i) are prepared bytreating the compounds of formula (1h) with a compound of formula (lVa).Although a solvent is not required, it is preferred that the reaction berun in lower alcohol such as methanol or ethanol or in excess compound(IVa). The temperature at which the reaction is carried out is notcritical, but the reaction is generally run at between about C to 100Cpreferably 40 to 50C. Although the time is not critical it is preferredthat the reaction be run for 1 to hours. The product is recovered byconventional techniques e.g. evaporation.

The compounds of formula (II) in which are prepared in accordance withthe following reaction scheme:

where R, R and R are as defined above.

The compounds of formula (llc) are prepared by treating a 4,6-diamino-Z-alkylsulfonyl-S- pyrimidinesulfonamide of formula (llb) withan amine of formula (IV). Although it is not necessary that the reactionbe carried out in a solvent, it is preferred that an inert hydroxylicsolvent such as water or lower alkanol or, where feasible, an excess ofamine (IV) be used. The temperature at which the reaction is run is notcritical although it is preferred that temperatures between roomtemperature and the reflux temperature of the reaction medium be used.The product is recovered by conventional means, e.g., evaporation.

The compounds of formula (II) in which R is hydrogen can be preparedfrom the compound of formula (llb) using the same procedure respectivelyas used to produce the compounds of formula (lg).

The compounds of formula (lb) and (lb') in which R is hydrogen or methylwhen R as previously defined, are known and can be prepared by theprocedure for preparing compounds (lb). Likewise, the compounds offormula (Ic) in which R is byis R"S- where R is 6 drogen or methyl whenA and B represent a carbon to nitrogen double bond or in which R ishydrogen when A and 8 both represent hydrogen are known and can beprepared by the procedures for preparing compounds (lb) and (la)respectively.

The compounds of formula (11) in which R is R (compound llb) or RS- andthe compounds of formula (Ill) and many of the compounds of formula(IV), (IVa) and (V1) are known and can be prepared by methods disclosedin the literature. The compounds of formula (IV), (lVa) and (V1) notspecifically disclosed in the literature can be prepared by analogousmethods from known starting materials.

The compounds of formula (I) are useful because they possesspharmacological activity in animals. In particular, the compounds areuseful as hypotensive/antihypertensive agents, as indicated by theiractivity in renal hypertensive rats given mg/kg of active compound usingthe techniques of A. Grollman (Proc. Soc. Expt. Biol. and Med. 57 102,1944) and indirectly measuring the blood pressure from the caudal arteryin the tail using a pneumatic pulse transducer.

When so utilized, the compounds may be combined with one or morepharmaceutically acceptable carrier or adjuvants. They may beadministered orally or parenterally and, depending upon the compoundemployed and the mode of administration, the exact dosage utilized mayvary.

Furthermore, the compounds of formula (I) may be similarly administeredin the form of their non-toxic pharmaceutically acceptable acid additionor alkali metal salts. Such salts possess the same order of activity asthe free base, are readily prepared by reacting the base with anappropriate acid or with an alkali metal alcoholate and accordingly, areincluded within the scope of the invention. Representative of the acidaddition salts are the mineral acid salts, such as the hydrochloride,hydrobromide, sulfate, phosphate and the like and the organic acidsalts, such as the succinate, benzoate, acetate, p-toluenesulfonate,benzenesulfonate, and the like. Representative of the alkali metal saltsare the lithium, sodium and potassium salts.

In general, satisfactory results are obtained when these compounds areadministered as a hypotensive/anti-hypertensive agent at a daily dosageof about 1.0 milligrams to about 200 milligrams per kilogram of animalbody weight p.o. This daily dosage is preferably administered 2 to 4times a day, or in sustained release form. For most large mammals, suchas primates, the total daily dosage is from about 75 milligrams to about1,000 milligrams. Dosage forms suitable for internal use comprise fromabout 18.5 milligrams to about 500 milligrams of the active compound inintimate admixture with a solid or liquid pharmaceutically acceptablecarrier or diluent.

A representative formulation suitable for oral administration is atablet or capsule prepared by standard encapsulating techniques whichcontain the ingredients indicated below and are useful in treatinghypertension at a dose of one tablet or capsule 2 to 4 times a day.Ingredient Weight (mg) magnesium stearate Total 300 mg.

Percent by Weight syrup elixir 8-amino-3-ethyl-6-methylthio-1,2,4-pyrimidin [4,5-e]

thiadiazinel l-dioxide (sodium salt) .5-3.5 -3.5 Buffering Systemquantity sufiicient to adjust pH Sodium Benzoate .l.5 .l.5 FlavoringAgent .0l-.2 .0l.2 Water 20-40 5-20 Simple syrups U.S.P. 30-70 0Sorbitol solution (70%) -30 -60 Certified Dye .5-2 .5-2 Alcohol 0 2.5-20Methyl Paraben 0 .05.] Propyl Paraben O .O5.l Sodium Saccharin 0 .Ol.08Alcohol 0 2.5-20 Methyl Paraben 0 .05.l Propyl Paraben 0 .O5.l SodiumSaccharin 0 .0l.08

EXAMPLE 1 8-amino-3-ethyl-6-methylthio-l ,2,4-pyrimido[4,5-elthiadiazine-l l -dioxide To 60.0 g of 4,6-diamino-2-methylthio-S-pyrimidinesulfonamide is added 900 ml of triethylorthopropionate and themixture is refluxed for 2 hours in an oil bath at l20130. Upon cooling,the 8-amino- 3-ethyl-6-methylthio-l,2,4pyrimido[4,5-e]thiadiazinel,1-dioxide precipitates and is filteredand recrystallized from methanol, mp 275-283.

When the above procedure is carried out using an equivalent amount of 14,6-diamino-2-methylsulfonyl-5- pyrimidinesulfonamide; 24,6-diamino-2-octylamino-5- pyrimidinesulfonamide; 3.4,6-diamino-2-ethylthio-5-pyrimidinesulfonamide or 4.4,6-diamino-5-pyrimidinesulfonamide in place of the4,6-diamino-2-methylthio-5- pyrimidinesulfonamide there is obtained 18-amino-3-ethyl-6-methylsulfonyll ,2,4-

pyrimido[4,5-e]thiadiazine-1,l-dioxide (m.p. 270-272C);

. 8-amino-3-ethyl-6-octylamino-l ,2,4-

pyrimido[4,5-e]thiadiazine-l ,l-dioxide;

3. 8-amino-3-ethyl-6-ethylthio-l,2,4-pyrimido[4,5-

e]thiadiazine-l ,1 -dioxide or 4. 8-amino-3-ethyl-l,2,4-pyrimido[4,5-e]thiadiazinel, l -dioxide (m.P. 330332C)respectively.

The above products are suspended in methanol and treated with sodiummethoxide to give the following sodium salts:

1. sodium-8-amino-3-ethyl-6-methylthio-l ,2,4-

pyrimido[4,5-e]thiadiazine-l,1-dioxide m.p. 3l7-3l9C).

sodium-8-amino-3-ethyl-6-methylsulfonyl-l ,2,4-pyrimido[4,5-e]thiadiazine-1,l-dioxide.

3. sodium-8-amino-3-ethyl-6-octylamino-l ,2,4-

pyrimido[4,5-e]thiadiazine-1,l-dioxide (m.p.

190-200C; monohydrate);

. sodium-8-amino-3-ethyl-6-ethylthio-l ,2,4-

pyrimido[4,5-e]thiadiazinel l -di0xide (m.p. 299302C) or 5.sodium-8-amino-3-ethyl-l ,2,4-pyrimido[4,5-

e]thiadiazine-1,l-dioxide.

When 8-amino-3ethyl-6-methylthio-l ,2,4-pyrimido[4,5-e]thiadiazine-1,l-dioxide is suspended in methanol andhydrogen chloride gas is bubbled through the mixture for one-half hours,there is obtained the hydrochloride salt of 8-amino-3-ethyl-6-methylthio-l,2,4-pyrimido[4,5-e]thiadiazine-l ,1- dioxide (m.p.278-280C).

EXAMPLE 2 When the process of example 1 is carried out using 60.0 gm of4,6-diamino-2-methylthio-5- pyrimidinesulfonamide and in place of the900 ml of triethylorthopropionate an equivalent amount of 1.triethylorthopentanoate 2. triethylorthochloroacetate 3.triethylorthobenzoate 4. triethylorthoisobutyrate 5.triethylorthobutyrate 6. triethylorthocyclopentanecarboxylate or 7.triethylorthocyclopropanecarboxylate there is obtained l.8-amino-3-butyl-6-methylthio-l ,2,4-pyrimido{4,5-

e]thiadiazine-l,l-dioxide (m.p. of sodium salt 298302C; monohydrate);

2. 8-amino-3-chloromethyl-6-methylthio-l ,2,4-

pyrimido[4,5-e1thiadiazine-l ,1 -dioxide (m.p. of sodium salt 305-3l0C;hemihydrate).

3. 8-amino-3-phenyl-6-methylthi0-l ,2,4-

pyrimido[4,5-e]thiadiazinel l -dioxide (m.p. 273278C); I

4. 8-amino-3-isopropyl-6-methylthio-l ,2,4-

pyrimido[4,5-e]thiadiazine-l,1 dioxide (m.p. of sodium salt 215-225C);

5. 8-amino-3-propyl-6-methylthio-l ,2,4-

pyrimido[4,5-e]thiadiazine-l,l-dioxide (m.p. of sodium salt 336-337C;hemihydrate);

6. 8-aminc-3-cyclopentyl-6-methylthio-l ,2,4-

pyrimido[4,5-e]thiadiazinel l -dioxide (m.p. 245247") or 7.8-amin0-3-cyclopropyl-6-methylthio-1 ,2,4-

pyrimido[4,5-e]thiadiazine-l l -dioxide (m.p. 245-250C; m.p. of sodiumsalt l200C) respectively.

EXAMPLE 3 4,6-diamino-2-morpholino-5pyrimidinesulfonamide To 3.6 g of4,6-diamino-2-methylsulfonyl-5- pyrimidinesulfonamide suspended in ml ofwater is added 4.1 g of morpholine. The mixture is stirred for 1 hour atreflux temperature, and thereafter stirred for an additional 17 hours atroom temperature. The solution is then filtered and dried to yield theproduct, 4,6- diamino-2-morpholino-5-pyrimidinesulfonamide; mp 233 C.(decomposition).

Following the above procedure but using piperazine in place of themorpholine used therein, there is obtained 4,6-diamino-2-piperazino-5-pyrimidinesulfonamide.

When an equivalent amount of 4,6-diamino-2-morpholino-5-pyrimidinesulfonamide or 4,6-diamino-2- piperazine-5-pyrimidinesulfonamide is usedin place of the 4,6-diamino-2-methylthio-5- pyrimidenesulfonamide in theprocess of Example 1, there is obtained 8-amino-3-ethyl-6-morpholino-l,2,4- pyrimido [4,5-e]thiadiazine-l,l-dioxide (m.p. of sodium salt297299 C) or 8-amino-3-ethyl-6- piperazino-l ,2,4-pyrimido[4,5-e1thiadiazine-l l dioxide, respectively.

When the process of example 1 is carried out using equivalent amounts of4,6-diamino-2-mopholino-5- pyrimidinesulfonamide andtriethyl-orthoformate in place of the 4,6-diamino-2-methylthio-S-pyrimidinesulfonamide and triethylorthopropionate used, there isobtained 8-amino-6-morpholino-l,2,4- pyrimido [4,5-e]thiadiazine-l,l-dioxide (mp. 287 to 290C).

EXAMPLE 4 4,6-diamino-Z-rnethylarnino-S-pyrimidinesulfonamide Into l2.0g of 4,6-diamino-2-methylsulfonyl-5- pyrimidinesulfonamide suspended in1900 ml of methanol is bubbled gaseous methylamine for 2 hours. Themixture is stirred at room temperature for an additional 15 hours andthen evaporated to dryness. The crude product is triturated in 35 ml ofmethanol, after which it is filtered and dried. Recrystallization frommethanol yields the product, 4,6-diamino-2-methylamio-5-pyrimidinesulfonamide, mp 199 201.

When diallylamine or aniline is used in place of methylamine in theprocess of this example, there is obtained 4,6-diamino-2-diallylamino-5-pyrimidinesulfonamide or 4,6-diamin-2-anilino-5- pyrimidinesulfonamide,respectively.

Following the procedure of Example 1 but using an equivalent amount of4,6-diamino-2-methylamino-5- pyrimidinesulfonamide;4,6-diamino-2-diallylamino-5- pyrimidinesulfonamide; or4,6-diamino-2-anilino-5- pyrimidine-sulfonamide in place of the4,6-diamino-2- methylthio-S-pyrimidenesulfonamide used therein, there isobtained 8-amino-3-ethyl-6-methylamino- 1,2,4-pyrimido [4,5-e]thiadiazine-l,1-dioxide (m.p. of HCl salt 235 to 248C);8-amino-3-ethyl-6- diallylamino-l ,2,4-pyrimido [4,5-e1thiadiazine-l ,1dioxide (m.p. 16ll62C) or S-amino-Zl-ethyl-G- anilino-l,2,4-pyrimido[4,5-e] thiadiazine-1,l-dioxide, respectively.

EXAMPLE 5 8-amino-3-ethyl-6-methylsulfonyll ,2,4-pyrimido[4,5-e]thiadiazine-l l -dioxide To a well stirred suspension of 32.0g of8-amino-3- ethyl--methylthio-l,2,4-pyrimido[4,5-e1thiadiazi'nel,l-dioxide prepared as in Example 1 in320 ml of acetic acid and 320 ml of acetic anhydride is added dropwise32 ml of 30 percent hydrogen peroxide. The temperature is maintainedbelow 90 C. by cooling in an ice bath. After about 1 1% hours, theproduct is precipitated by cooling and separated by filtration. Theproduct, 8- amin0-3-ethyl6-methylsulfonyl-1,2,4-pyrimido[4,5-e]-thiadiazine-l,l-dioxide (mp 270272C., decomposition) is recovered byrecrystallization from methanol.

EXAMPLE 6 8-amino-3-methyl-6-methylsulfonyl-l ,2,4- pyrimido[4,5-e1thiadiazine-l 1 -dioxide To 5.0 g of8-amino-3-methyl-6-methylthio-l,2,4- pyrimido[4,5-e]thiadiazine-l,l-dioxide suspended in 150 ml of glacial acetic acid and150 ml of acetic anhydride is added dropwise 5 ml of 30 percent hydrogenperoxide. The reaction mixture is stirred overnight at room temperatureand the precipitated 8-amino-3- methyl-fi-methylsulfonyl-l,2,4-pyrimido[4,5-e] thiadiazine-l,l-dioxide is recovered by filtration,mp 285 287.

When an equivalent amount of 8amino 6- methylthio-l,2,4-pyrimido[4,5-e]thiadiazinel l dioxide is used in. place of the8-amino-3-methyl-6- methylthio-l ,2,4-pyrimido( 4,5-e]thiadiazine-l ldioxide in the above process, there is obtained 8-amino-6-methylsulfonyll ,2,4-pyrimido[4,5 -e]thiadiazine- 1 1 -dioxide.

EXAMPLE 7 8-arnino-3methyl-o-methylamino-l ,2,4-pyrimido{ 4,5-e]t.hiadiazine-l l -dioxide hydrochloride Three grams of8-arnino-3-methyl-6-methylsulfonyl- 1,2,4-pyrimido[4,5-e]thiadiazine-l,l-dioxide is suspended in 200 ml of methanol andmethylamine gas is bubbled through the suspension for 15 minutes. Mostof the solvent is then removed, and the precipitate 8-amino-3-methyl-6-methylamino-l ,2,4-pyrimido[4,5-e]thiadiazine-l,l-dioxide (mp 338-339 d.) is filtered off andrecrystallized from methanol.

Into a suspension of L2 g of this material in 35 ml of methanol isbubbled hydrogen chloride gas for l0 minutes. The precipitate whichforms on cooling is filtered off to yield8-amino-3-methyl-6-methylamino-l ,2,4- pyrimido[4,5-e]thiadiazine-l,1-dioxide hydrochloride; (mp 332 334 C. d.).

When an equivalent amount of 8-amino-6- methylsulfonyl-l,2,4-pyrimido[4,5-e]thiadiazinel l dioxide is used in place of the8-amino-3 methyl-6- methylsulfonyl-l ,2,4-pyrimido{4,5-elthiadiazine l ldioxide in the above process there is obtained 8-amino- 6-methylaminol,2,4-pyrimid,o 4,5-e]thiadiazine-l l dioxide.

EXAMPLE 8 8-amino-3-ethyl-6-methylamino-l ,2,4-pyrimido[ 4,5-elthiadiazine-l l -dioxide hydrochloride Ten grams of8-amino-3-ethyl-6-methylsulfonyl- 1,2,4-pyrimido[4,5-e]thiadiazine-l,l-dioxide is suspended in 600 ml of methanol andmethylamine gas is bubbled through the suspension for 30 minutes.Cooling and filtration yields 8-amino-3-ethyl-6-methylamino-l,2,4-pyrimido[4,5-e1thiadiazine-1,1- dioxide.

Into a suspension of 5.8 g of this material in 200 ml of methanol isbubbled hydrogen chloride gas for 15 minutes, until a clear solutionforms. The majority of the solvent is then removed by evaporation andether is added to precipitate 8-amino-3-ethyl-6- methylaminol,2,4-pyrimido [4,5-e1thiadiazine-l l dioxide hydrochloride (mp 235 248C. d.).

When the above procedure is carried out and equivalent amounts ofdiallylamine, aniline, morpholine or piperazine are used in place of themethylamine used therein, there is obtained the hydrochloride salt of 8-amino-3-ethyl-6-diallylamino-l ,2,4-pyrimido[ 4,5 elthiadiazine-l l-dioxide; 8-amino-3-ethyl-6-anilinol ,2,4-pyrimido[4,5-e1thiadiazinel l-dioxide; 8- amino-3-ethyl-6-morpholino-l ,2,4-pyrimido[4,5-e]thiadiazine-1,l-dioxide or 8-amino-3 -ethyl-6- piperazine-l,2,4pyrimido[4,5-eIthiadiazinel l dioxide, respectively.

EXAMPLE 9 8-amino-3 ,4-dihydro-3-methyl-6-methylthio-1,2,4-pyrimido[4,5-e]thiadiazine-1,l-dioxide.

To 7.3 g of sodium borohydride dissolved in 200 ml of water is slowlyadded 20.0 g of 8-amino-3-methyl-6-methylthio-l,2,4-pyrimido[4,5-e]thiadiazine-1,1- dioxide. After theaddition is complete, the reaction mixture is heated at 90 for 48 hours.On cooling, the product, 8-amino-3,4-dihydro-3-methyl-6-methylthio-1,2,4-pyrimido[4,5-elthiadiazine-1,l-dioxide precipitates and isrecovered by filtration (mp 228-229C, m.p. of HCl salt 2l3215C).

When an equivalent amount of 8-amino-3-ethyl- 1,2,4-pyrimido[4,5-e]thiadiazine-1,l-dioxide; 8-amino-3-ethyl-6-methylthio-1,2,4-pyrimido[4,5- e]thiadiazine-1 ,1-dioxide; 8-amino-6-methylamino- 1,2,4-pyrimido [4,5-e]thiadiazine- 1 1-dioxide; 8- amino-3-methyl-6-methylamino-l ,2,4,-pyrimido[4,5-e]thiadiazinel 1 -dioxide; 8-amino-3-ethyl-6- methylamino-l,2,4-pyrimido[4,5-e]thiadiazine-1,1- dioxide;8-amino-3-ethyl-6-diallylamino-l ,2,4-pyrimido[4,5-e]thiadiazine-1,l-dioxide; 8-amino-3-ethyl-6-anilino-1,2,4-pyrimido[4,5-e]thiadiazine-1,1- dioxide;8-amino-3-ethyl-6-morpholino-1,2,4-pyrimido[4,5-e]thiadiazine-l,l-dioxide or 8-amino-3-ethyl-6-piperazino-1,2,4-pyrimido[4,5-e] thiadiazine- 1,1-dioxide isused in place of 8-amino-3-ethyl-6-methylthio-l,2,4-pyrimido[4,5-e]thiadiazine-1,1- dioxide in the aboveprocess there is obtained S-amino- 3,4-dihydro-3-ethy1-1,2,4-pyrimido[4,5-e1thiadiazine- 1,1-dioxide; (m.p. of sodium salt 220-225C;dihydrate);8-amino-3,4-dihydro-3-ethyl-6-methylthiol,2,4-pyrimido[4,5-e]thiadiazine-1,l-dioxide;(m.p. of sodium salt 194 to 196C; monohydrate); 8-amino-3,4-dihydro-6-methylamino-1,2,4-pyrimido[4,5- e]thiadiazine-1 ,1-dioxide; 8-amino-3 ,4-dihydro-3-methyl-6-methylamino-1,2,4-pyrimido[4,5-e]thiadiazine-1,1-dioxide;8-amino-3 ,4-dihydro-3-ethyl-6-methylamino-l,2,4-pyrimido[4,5-e]thiadiazine-1,1- dioxide;8-amino-3,4-dihydro-3-ethyl-6-diallylamino- 1,2,4-pyrimido[4,5-e]thiadiazine-1,1-dioxide; Samino- 3 ,4-dihydro-3-ethy1-6-anilino-l,2,4-pyrimido[4,5- e]thiadiazine-1,1-dioxide; 8-amino-3 ,4-dihydro-3-ethyl-morpholino-l ,2,4-pyrimido[4,5-e]thiadiazine- 1,1-dioxide (m.p. ofsodium salt 232242C, monohydrate) or8-amino-3,4-dihydro-3-ethy1-6-piperizino-1,2,4-pyrimido[4,5-e]thiadiazine-1 1 -dioxide, respectively.

EXAMPLE 10 8-Amino-3 ,4-dihydro-3-methyl-6-methylsulfonyl-1,2,4-pyrimido[4,5-e]thiadiazine-1,l-dioxide Following the procedure ofExample 5 but using an equivalent amount of8-amino-3,4-dihydro-3-methyl-6-methylthio-l,2,4-pyrimido[4,5-e]thiadiazine-1,1- dixoide or8-amino-3,4-dihydro-6-methylthio-1,2,4- pyrimido[4,5-e1thiadiazine-l,l-dioxide in place of the8-amino-3-ethy1-6-methylthio-1,2,4-pyrimido[4,5-e]thiadiazine-1,l-dioxide used therein, there is obtained8-amino-3,4-dihydro-3-methyl-6- methylsulfonyl-l,2,4-pyrimido[4,5-e]thiadiazine-1,ldioxide or8-amino-3,4-dihydro-6-methy1su1fonyll,2,4-pyrimido[4,5-e]thiadiazine-1,l-dioxiderespectively. When 8-amino-3,4-dihydro-3-methyl-6-methylsulfonyl-l,2,4-pyrimido[4,5-e]thiadiazine-1 ,1- dioxide is treatedwith methylamine in accordance with the process of Example 6, there isobtained 8-amino- 3,4-dihydro-3-methyl-6-methylamino-1,2,4-pyrimido[4,5-e]thiadiazine-1,l-dioxide.

EXAMPLE 1 1 8-amino-3-cyclopropyl-6-methy1thio-l ,2,4-pyrimido [4,5 -e]thiadiazinel 1 -dioxide Step A: 6-amino-cyclopropanecarbonylamido-2-methylthio-S-pyrimidinesulfonamide To 1 1.76 of4,6-diamino-2-methylthio-5- pyrimidinesulfonamide dissolved in 300 ml.of tetrahydrofuran is added dropwise 5.6 g. of cyclopropane carbonylchloride. The mixture is stirred while refluxing for 4 days followingwhich the crystals are filtered and the tetrahydrofuran solutionevaporated to dryness. The residue is washed with 20 ml of ether, 30 ml.of tetrahydrofuran, 50 ml of water and ml of methanol and then dried toobtain 1.2 g of the product; m.p. 21 1-214C.

Step B: 8-amino-3-cyclopropyl-6-methylthio-1,2,4-pyrimido-[4,5-elthiadiazine-1,1-dioxide In a round bottom flask isplaced 0.979 g. of 6-amino- 4-cyclopropanecarbonylamido-Z-methylthio-S-pyrimidinesulfonamide which is then heated to 240 in an oil bath. Aquantitative yield of the product is obtained, m.p. 245-250C.

The sodium salt was prepared by suspension in methanol and addition ofsodium methoxide. Recrystallization from ethanol gave sodium 8-amino-3-cyclopropyl-G-methylthiol ,2,4-pyrimido-[4,5- elthiadiazine 1,1-dioxidehemihydrate, m.p. 190200- Following the above procedure but using anequivalent amount of propionyl chloride or butyryl chloride in place ofthe cyclopropane carbonyl chloride, there is obtained6-amino-4-propionylamido-2-methylthio-S- pyrimidinesulfonamide or6-arnino-4-butyrylamido -2- methylthio-S-pyrimidinesulfonamiderespectively before heating and 8-amino-3-ethyl-6-methylthio-l,2,4-pyrimido-[4,5-e]thiadiazine-1,1-dioxide or 8-amino-3- propyl-6methylthio-l,2,4-pyrimido [4,5-e] thiadiazine-1,1-dioxide respectivelyafter heating.

EXAMPLE 12 Sodium-8-amino-3-cyclopentyl-6-methylthio-1 ,2,4-pyrimido-[4,5 -e]thiadiazinel 1 -dioxide Step A:6-amino-4-cyclopentanecarbonylamido-2-methylthio-S-pyrimidinesu1fonamide To 19.5 g. of oxalyl chloride isadded slowly at room temperature 17.4 g. of cyclopentane carboxylicacid. The solution is stirred at room temperature for 15 minutes andthen at l00for 30 minutes. To this mixture is added 5.0 g. of finelypowdered 4,6-diamino-2- methylthio-S-pyrimidinesulfonamide. Thereactants are heated at 100 for 1.5 hours, at for 3 hours and at for 9hours. The mixture is then cooled to room temperature and the crystalsfiltered and washed with ether. Recrystallization from methanol-etheryields the title product (m.p. 219-221C). Step B:Sodium-8-amino-3-cyclopentyl-6-methylthiol,2,4-pyrimido-[4,5-e]thiadiazine-1,l-dioxide To 3.8 g. of6-amino-4-cyclopentanecarbonylamido-2-methylthio-S-pyrimidine-sulfonamide is added 700 ml. of 28 percentammonium hydroxide solution. The mixture is heated at 105 for 9 hoursfollowing which it is concentrated under vacuum. The title product isobtained by filtration (m.p. 245-247).

On treatment of 2.0 g. of this 8-amino-3-cyclopentyltS-methylthiol,2,4-pyrimido[4,5-e]thiadiazine 1,1- dioxide with sodium methoxide inmethanol, the hemihydrate of the sodium salt is obtained, (m.p. 325).

When the above process is carried out and an equivalent amount ofpropionic acid, isobutyric acid or cyclopropyl carboxylic acid is usedin place of the cyclopentane carboxylic acid, there is obtained beforeheating in base 6-amino-4-propionylamido-2-methylthio-5-pyrimidinesulfonamide; 6-amino-4-isobutyrylamido-2-methylthio-S-pyrimidinesulfonamide or 6-amino-4-cyclopropylcarbonylamido-2-rnethylthio-5- pyrimidinesulfonamiderespectively and after heating in a strong base there is obtained8-amino-3-ethyl-6- methylthio-l ,2,4-pyrimido [4,5-e1thiadiazine-l ,1-dioxide; 8-amino-3-isopropyl-6methylthiol,2,4pyrimido[4,5-e1thiadiazine-l,l-dioxide or 8-amino-3-cyclopropyl-6-methylthio-1,2,4-pyrimido [4,- 5-e]thiadiazine-1 l-dioxide respectively. EXAMPLE l3 8-amino-3-ethyl-3 ,4-dihydro-l,2,4-pyrimido[ 4,5- elthiadiazinel l -dioxide To a suspension of 15.0gms of 8-amino-3-ethyl-6- methysulfonyl -l,2,4-pyrimido [4,5-e]thiadiazine -l,ldioxide is added slowly 8.0 g of sodium borohydride. Thereaction mixture is stirred for 1 hour at room temperature after whichthe title product is isolated by filtration and dried (m.p. of thesodium salt dihydrate 220-225C) EXAMPLE l4 where R represents hydrogen,lower alkyl, phenyl, cycloalkyl having three to six carbon atoms,

R9 R --Cl or RTN where R represents lower alkyl and R and R eachindependently represent hydrogen or lower alkyl and R representshydrogen, RS-,R"SO or where R represents lower alkyl; and R and R eachindependently represent hydrogen,

alkyl having one to eight carbon atoms,alkenyl having three to fivecarbon atoms, phenyl or R and R together with N represents j z N- whereZ is O or and A and B each represent hydrogen or A and B togetherrepresent a carbon to nitrogen bond, provided that when R. is RS and Aand B together represent a carbon to nitrogen double bond, R is otherthan hydrogen or methyl; and that when R is RS- and A and B are bothhydrogen or when R is hydrogen and A and B together represent a carbonto nitrogen double bond, R is other than hydrogen; or a pharmaceuticallyacceptable acid addition or alkali metal salt thereof.

2. A compound, according to claim 1 in which R is lower alkyl having 2to 4 carbon atoms, phenyl, cycloalkyl having three to six carbon atoms,R'-Cl or R is RSand A and B together represents a carbon to nitrogenbond where R, R, R" and R are as defined in claim 1 or apharmaceutically acceptable acid addition or alkali metal salt thereof.3. The compound of claim 1 which is 8-amino-3- ethyl--methyl-sulfonyl-l,2,4-pyrimido[4,5 -e ]thiadiazine-1,1-dioxide.

- ethyl-o-methylthio-l,2,4-pyrimido[4,5-e]thiadiazinel, l -dioxide.

9. The compound of claim 2 which is 8-amino-3- isopropyl-6-methylthio-l,2,4-pyrimido[ 4,5-e]thiadiazine-1,1-dioxide.

10. The compound of claim 2 which is 8-amino-3- butyl-6-methylthio-l,2,4-pyrimido[4,5-e]thiadiazine- 1,1-dioxide.

11. A process for producing a compound of the formula which comprisestreating a compound of the formula with a compound of the formula(RO),C-R"

where R" represents hydrogen, lower alkyl, phenyl, cycloalkyl havingthree to six carbon atoms or R- -Cl, R is straight chain lower alkylhaving one to three carbon atoms; and R are as defined in claim 1,provided R" is other than hydrogen or methyl when R is RS as defined inclaim 1. r 12. A process for producing a compound of the formula 50 f\/N NH l II J which comprises treating in a polar solvent a compound ofthe formula with a compound of the formula 20 where Y is hydroxy or halohaving an atomic weight of about 35 to 80; provided that when Y ishydroxy, the process is carried out in the presence of oxalyl chlorideor oxalyl bromide to form an intermediate of the formula sown, 1/ r 1 Uaw RV RN/s and thereafter cyclizing said intermediate by heating where40 R is hydrogen, lower alkyl, cycloalkyl having three to six carbonatoms or RCl; R is hydrogen, R 8, R 80 or N and R R, R, R and theproviso are as set out in claim 1 with the'added proviso that at leastone of R or R is other than hydrogen.

2. A compound, according to claim 1 in which R1 is lower alkyl having 2to 4 carbon atoms, phenyl, cycloalkyl having three to six carbon atoms,-R7-Cl or
 3. The compound of claim 1 which is8-amino-3-ethyl-6-methyl-sulfonyl-1,2,4-pyrimido(4,5-e)thiadiazine-1,1-dioxide.
 4. The compound of claim 1 which is8-amino-3-methyl-6-methyl-sulfonyl-1,2,4-pyrimido(4,5-e)thiadiazine-1,1-dioxide.
 5. The compound of claim 1 which is8-amino-3-methyl-6-methylamino-1,2,4-pyrimido(4,5-e)thiadiazine-1,1-dioxide.6. The compound of claim 1 which is8-amino-3-ethyl-6-methylamino-1,2,4-pyrimido-(4,5-e)thiadiazine-1,1dioxide.7. The compound of claim 1 which is 8-amino-3,4-dihydro-3-ethyl-6-methylthio-1,2,4-pyrimido(4,5-e)thiadiazine-1,1-dioxide.
 8. Thecompound of claim 2 which is8-amino-3-ethyl-6-methylthio-1,2,4-pyrimido(4,5-e)thiadiazine-1,1-dioxide.9. The compound of claim 2 which is8-amino-3-isopropyl-6-methylthio-1,2,4-pyrimido(4,5-e)thiadiazine-1,1-dioxide.
 10. The compound of claim 2 which is8-amino-3-butyl-6-methylthio-1,2,4-pyrimido(4,5-e)thiadiazine-1,1-dioxide.11. A process for producing a compound of the formula
 12. A process forproducing a compound of the formula